• MARWA T. HASSEN Department of Zoology, Faculty of Women for Arts, Science and Education, Ain Shams University, Cairo, Egypt
  • NAJAT JABBAR AHMED Erbil Technical Health College, Erbil Polytechnic University, Erbil, Iraq
  • HANAA K. MOHAMED Department of Zoology, Faculty of Women for Arts, Science and Education, Ain Shams University, Cairo, Egypt


Objective: Hepatic cancer is known as primary liver cancer and hepatocellular carcinoma (HCC). Newly silver nanoparticles gained importance due to its advantages and multiple potential such as molecular imaging agent, antimicrobial, wound healing, anti-inflammatory and anticancer activity. The current study deals to assess therapeutic property silver nanoparticles (AgNPs) against diethylnitrosamine (DENA), and carbon tetrachloride (CCL4) induced hepatic cancer.

Methods: Thirty male albino rats (200-250g) were distributed into four groups and hepatic cancer was induced with a single intraperitoneal dose of 200 mg/kg body weight of DENA. Two weeks later, animals received subcutaneous injections of CCl4 once a week in a dose of 3 ml/kg body weight for 6weeks. Serum biomarkers, antioxidants enzymes, inflammatory markers were evaluated to find the anti-proliferative potential of silver nanoparticles. Histological evaluation and microscopic reports were also done to document the results of the current work.

Results: AgNPs significantly recover the serum marker enzymes of hepatic parameter AST, ALT, ALP, and total bilirubin and also decreased the levels of NO, IL-6 and TNF-α. Histopathological features also exhibited recovery of a hepatic architecture in cancer-induced rats. Moreover, the immunohistochemical investigation demonstrated that the levels of PCNA, and Caspase-3, which are hepatocarcinogenic markers, were significantly improved by AgNPs.

Conclusion: These results concluded that AgNPs showed promising curing effects on hepatocellular ailments.

Keywords: Hepatocellular carcinoma (HCC), Diethylnitrosoamine (DENA), Carbon tetrachloride (CCL4), Silver nanoparticles (AgNPs), Apoptosis, Interleukin-6(IL-6)


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1. Zhu RX, Seto WK, Lai CL, Yuen MF. Epidemiology of hepatocellular carcinoma in the asia-pacific region. Gut Liver 2016;10:332.
2. Mishra S, Hora S, Shukla V, Das M, Kharkwal H, Katare DP. Sustained release tablets of sorafenib-silibinin combinations for the treatment of hepatocellular carcinoma. Int J Appl Pharm 2018;10:117-24.
3. Ding Y, Peng Z, Ding L, Peng Y. Baishouwu extract suppresses the development of hepatocellular carcinoma via TLR4/MyD88/NF-kB. Pathway 2019;10:1-14.
4. Ramakrishnan G, Augustine T, Jagan S, Vinodhkumar R, Devaki T. Effect of silymarin on N-nitrosodiethylamine induced hepatocarcinogenesis in rats. Exp Oncol 2007;29:39-44.
5. Wang F, Qu W, Li Y, Liu H, Li B, Qi J, et al. Diethyl nitrosamine alone was not recommended for primary hepacellular carcinoma model in rats. Int J Clin Exp Pathol 2016;9:10346-50.
6. Uehara T, Ainslie GR, Kutanzi K, Pogribny IP, Muskhelishvili L, Izawa T, et al. Molecular mechanisms of fibrosis-associated promotion of liver carcinogenesis. Toxicol Sci 2013;132:53-63.
7. Muto J, Shirabe K, Sugimachi K, Maehara Y. Review of angiogenesis in hepatocellular carcinoma: Angiogenesis in hepatocellular carcinoma. Hepatol Res 2015;45:1–9.
8. Satyavani K, Gurudeeban S, Balasubramanian TR. Biomedical potential of silver nanoparticles synthesized from calli cells of Citrullus colocynthis(L.) Schrad. J Nanobiotechnol 2011;9:43.
9. Reshi MS, Uthra C, Yadav D, Sharma S, Singh A, Sharma A, et al. Silver nanoparticles protect acetaminophen-induced acute hepat otoxicity: a biochemical and histopathological approach. Regulatory Toxicol Pharmacol 2017;90:364.
10. Priyadarshni KC, Mahalingam PU. Antimicrobal and anticancer activity of silver nanoparticles from edible mushroom: a review. Asian J Pharm Clin Res 2017;10:37-40.
11. Gurunathan S, Lee KJ, Kalishwaralal K, Sheikpranbabu S, Vaidyanathan R, Eom SH. Antiangiogenic properties of silver nanoparticles. Biomaterials 2009;30:6341–5.
12. Kalishwaralal K, Banumathi E, Pandian SRK, Deepak V, Muniyandi J, Eom SH, et al. Silver nanoparticles inhibit VEGF induced cell proliferation and migration in bovine retinal endothelial cells. Colloids Surf B Biointerfaces 2009;73:51–7.
13. Zhu B, Lin N, Zhang M, Zhu Y, Cheng H, Chen S, et al. Activated hepatic stellate cells promote angiogenesis via interleukin-8 in hepatocellular carcinoma. J Transl Med 2015;13:365.
14. Hader A, Aqel M, Hasan Z. Hypoglycemic effects of the volatile oil of Nigella sativa seeds. Pharmaceutical Biol 1993;31:96-100.
15. Kalus U, Pruss A, Bystron J, Jurecka M, Smekalova A, Lichius JJ, et al. Effect of Nigella sativa (black seed) on subjective feeling in patients with allergic diseases. Phytother Res 2003;17:1209-14.
16. Bourgou S, Pichette A, Marzouk B, Legault J. Antioxidant, anti-inflammatory, anticancer and antibacterial activities of extracts from Nigella sativa (Black cumin) plant parts. J Food Biochem 2012;36:539-46.
17. Motawi TK, El-Boghdady NA, El-Sayed AM, Helmy HS. Comparative study of the effects of PE gylated interferon-?2a versus 5-fluorouracil on cancer stem cells in a rat model of hepatocellular carcinoma. Tumor Biol 2016;37:1617–25.
18. Sarkar A, Basak R, Bishayee A, Basak J, Chatterjee M. B-Carotene inhibits rat liver chromosomal aberrations and DNA chain break after a single injection of diethylnitrosamine. Br J Cancer 1997;76:855–61.
19. Dakshayani KB, Subramanian P, Manivasagam T, Mohamed EM, Manoharan S. Melatonin modulates the oxidant–antioxidant imbalance during N-nitrosodiethylamine induced hepatocarcinogenesis in rats. J Pharm Pharm Sci 2005;8:316-21.
20. Bergmeyer HU, Scheibe P, Wahlefeld AW. Optimization of methods for aspartate aminotransferase and alanine aminotransferase. Clin Chem 1978:24:58–73.
21. Belfield A, Goldberg D. Colorimetric determination of alkaline phosphatase activity. Enzym 1971;12:561-6.
22. Walter M, Gerade H. A colorimetric method for determination of bilirubin in serum and plasma. Micro Chem J 1970;15:231–6.
23. Chan YH. Biostatistics102: quantitative data–parametric and non-parametric tests. Singapore Med J 2003;44:391-6.
24. Singh A, Dar MY, Joshi B, Sharma B, Shrivastava S, Shukla S. Phytofabrication of silver nanoparticles: novel drug to overcome hepatocellular ailments. Tox Rep 2018;5:333-42.
25. Al-Rejaie SS, Aleisa AM, Al-Yahya AA. Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats. World J Gastroenterol 2009;15:1373-80.
26. Erejuwa OO, Sulaiman SA, Wahab MS, Sirajudeen KNS, Salleh MS, Gurtu S. Hepatoprotective effect of tualang honey supplementation in streptozotocin-induced diabetic rats. Int J Appl Res Nat Prod 2011;463:39–44.
27. Singha D, Singhb M, Yadava E, Fallsc N, Dangid DS, Kumarc V, et al. Attenuation of diethylnitrosamine (DEN)–Induced hepatic cancer in experimental model of wistar rats by Carissa carandas embedded silver nanoparticles. Biomed Pharmacother 2018;108:757–65.
28. Pal S, Bhattacharjee A, Mukherjee S, Bhattacharya K, Mukherjee S, Khowala S. Effect of alocasia indica tuber extract on reducing hepatotoxicity and liver apoptosis in alcohol intoxicated rats. Biomed Res Int 2014:10.
29. Rajkapoor B, Jayakar B, Murugesh N, Sakthiskaran D. Chemoprevention and cytotoxic effect of Bauhinia variegata against N-nitrosodiethylamine induced liver tumors and human cancer cell lines. J Ethnopharmacol 2006;104:407-9.
30. Porta C, De Amici M, Quaglini S, Paglino C, Tagliani F, Boncimino A, et al. Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Ann Oncol 2008;19:353-8.
31. ?ukaszewicz M, Mroczko B, Szmitkowski M. Clinical significance of interleukin-6 (IL-6) as a prognostic factor of cancer disease. Pol Arch Med Wewn 2007;117:247-51.
32. Jin X, Zimmers TA, Perez EA, Pierce RH, Zhang Z, Koniaris LG. Paradoxical effects of short and long-term interleukin-6 exposure on liver injury and repair. Hepatology 2006;43:474–84.
33. El-Houseini ME, Mohammed MS, Elshemey WM. Enhanced detection of hepatocellular carcinoma. Cancer Control 2005;12:248–53.
34. Tan A, Kim R, El-Gazzaz G. Serum vascular endothelial growth factor level in patients with hepatocellular carcinoma undergoing liver transplantation: experience of a single Western center. Int J Organ Transplant Med 2012;3:42–51.
35. Darvesh AS, Aggarwal BB, Bishayee A. Curcumin and liver cancer: a review. Curr Pharm Biotechnol 2012;13:218–28.
36. Talaat RM, Adel S, Salem TA, Nasr MI. Correlation between angiogenic/inflammatory mediators in Wister rat model of liver dysplasia. J Immunoassay Immunochem 2016;37:472–84.
37. Aboubakr EM, Taye A, Aly OM, Gamal-Eldeen AM, El-Moselhy MA. Enhanced anticancer effect of combretastatin A-4 phosphate when combined with vincristine in the treatment of hepatocellular carcinoma. Biomed Pharmacother 2017;89:36-46.
38. Otto W, Sierdzinski J, Krol M, Wolinska E, Feliksbrot Bratosiewicz M, Wilkowojska U. Thvalue of tumor angiogenesis activity for stratification of HCC patients. Int J Clin Exp Med 2017;10:4200–13.
39. Barretto OC, Zyngier SB. Acquired disturbance of erythrocyte glutathione reductase in experimental tumors. J Cancer Res Clin Oncol 1984;108:252–3.
40. Jim JH, Jung JH, Kim SS, Yoon JU, Park JD, Choi BS. Twenty-eight-day inhalation toxicity study of silver nanoparticles in sprague dawley rats. Inhal Toxicol 2007;19:857–71.
41. Freudenthal BD, Ramaswamy S, Hingorani MM, Washington MT. Structure of a mutant form of proliferating cell nuclear antigen that blocks translation DNA synthesis. Biochemistry 2008;47:13354–61.
42. Maga G, Hubscher U. Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci 2003;116:3051–60.
43. Lehmann AR, Fuchs RP. Gaps and forks in DNA replication: rediscovering old models. DNA Repair 2006;5:1495–8.
44. Czyzewska J, Guzinska Ustymowicz K, Lebelt A, Zalewski B, Kemona A. Evaluation of proliferating markers Ki-67, PCNA in gastric cancers. Rocz Akad Med Bialymst 2004;49:64–6.
45. Li J, Yuan J. Caspases in apoptosis and beyond. Oncogene 2008;27:6194–206.
46. Jones JR, Kong L, Hanna MGIV, Hoffman B, Krencik R, Bradley R, et al. Mutation in GFAP disrupt the distribution and function of organelle in humanastrocytes. Cell Report 2018;25:947–58.
47. D’Amelio M, Cavallucci V, Cecconi F. Neuronal caspase-3 signaling: not only cell death. Cell Death Differ 2010;17:1104–14.
48. Vaidyanathan R, Kalishwaralal K, Gopalram S, Gurunathan S. Nano silver-the burgeoing therapeutic molecule and its green synthesis. Biotechnol Adv 2009;27:924-37.
49. Tabone M, Pellicano R. Prevention of intrahepatic hepato-carcinoma recurrence in patients with viral cirrhosis: two potential options. Minerva Gastroenterol Dietol 2006;52:47-52.
50. Antony JJ, Sithika MAA, Joseph TA, Suriyakalaa U, Sankarganesh A, Siva D, et al. In vivo antitumor activity of biosynthesized silver nanoparticles using ficus religiosa as a nanofactory in DAL induced mice model. Colloids Surf B 2013;108:185-90.
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How to Cite
HASSEN, M. T., N. J. AHMED, and H. K. MOHAMED. “THERAPEUTIC EFFECT OF SILVER NANOPARTICLES AGAINST DIETHYL NITROSAMIN AND CARBON TETTRACHLORIDE-INDUCED HEPATOCELLULAR CARCINOMA IN RATS”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 12, no. 9, July 2020, pp. 1-8, doi:10.22159/ijpps.2020v12i9.38813.
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